The research objective of this proposal is to define the molecular distinctions between prognostically distinct subsets of limited-stage FL, in order to improve therapeutic algorithms. Irrespective of the therapeutic approach, approximately 60% of cases remain localized and never progress, while the remainder of cases ultimately progress to more aggressive lymphoma. Currently, oncologists have no way of distinguishing the cases that will ultimately progress from those that will remain localized. Nevertheless, 40% of these patients are treated with aggressive chemotherapy on the basis of imprecise algorithms despite the toxicities associated with this treatment. Thus, there is a critical need to obtain more accurate indicators of outcome on which to base therapeutic decisions. We aim to define the molecular alterations that may distinguish two subgroups of FL that we believe are prognostically and biologically distinct. The results of this proposal will significantly impact lymphoma management, as it would identify a cohort of patients may potentially be spared the toxic effects of radiation and/or aggressive chemotherapy. My overall goal for this training period is to become an independently funded clinical investigator with an innovative clinical research program in patient-oriented lymphoma research. Over the past two years since joining the MGH Pathology faculty, I have received tremendous support from my chairman, Dr. Louis, in my effort to work towards my career and research objectives. Completion of the studies proposed will provide the substrate for me to develop the appropriate skills necessary for me to achieve this goal with the mentorship of Dr. Shiv Pillai and Dr. Nancy Harris and the rest of my advisory committee. Dr. Pillai is internationally known for his expertise in the biology of autoimmunity and lymphomagenesis. He is also famous for the quality of his mentorship. We have collaborated on the identification of novel mutations in adult FL using deep sequencing technology. Dr. Harris is one of the most distinguished experts in lymphoma diagnosis, classification and investigation, with worldwide recognition by both pathologists and lymphoma oncologists. Together with the rest of my advisory team, Dr. Pillai and Dr. Harris will provide the perfect blend of mentorship to guide my development to an independent investigator specifically in patient-oriented lymphoma research. I anticipate that the results obtained from the proposed studies will enhance our understanding of FL biology, while forming a solid foundation on which to launch my career as a clinical investigator. I believe that with my background in basic and clinical research, my experience in clinical hematopathology, combined with the clinical material, resources and network of expert clinical and research mentors currently available to me at MGH, the K23 award would make me uniquely situated to accomplish my career and research objectives.